PON1 polymorphisms are predictors of ability to attain HDL-C goals in statin-treated patients.

OBJECTIVES: PON1 plays an important role in inhibiting LDL-C oxidation, which reduces atherosclerosis and cardiovascular disease. Elevated PON1 activity or levels may contribute to increased HDL-C levels, but controversy exists over the hypothesis that genetic variation in the PON1 gene locus modulates HDL-C levels and responses to statin treatment. Therefore, the objective of this study was to investigate the association between two polymorphisms in the PON1 gene and statin responses in a south Brazilian population. DESIGN AND METHODS: The study population included 433 dyslipidemic patients who were prescribed statins. Total cholesterol, triglyceride, HDL-C and LDL-C levels were measured in these patients both before and after approximately 6months of treatment with simvastatin/atorvastatin. Genotypes were assessed by real-time PCR for two PON1 polymorphisms, Q192R (rs662) and L55M (rs854560). RESULTS: Baseline lipid levels were not associated with Q192R or L55M polymorphisms. For the Q192R (rs662) polymorphism, we observed that HDL-C goals were attained less often in patients with RR homozygosity than in Q allele carriers (χ(2) P=0.009, adjusted residual analysis P=0.003). For the L55M (rs854560) polymorphism, LL homozygotes were underrepresented among subjects that achieved the HDL-C goal (χ(2) P=0.026, adjusted residual analysis P=0.008). Analysis by univariate logistic regression confirmed that QQ/QR and MM/ML carriers had an increased chance of attaining HDL-C goals (OR=2.41, CI95%=1.32-4.40, P=0.004 and OR=1.68, CI95%=1.15-2.45, P=0.008). In a multivariate logistic analysis used to assess predictors of attaining an HDL-C goal>1.55mmol/L, we observed that gender (OR=1.71, CI95%=1.04-2.83, P=0.036), baseline HDL-C levels (OR=1.13, CI95%=1.10-1.16, P<0.001) and the QQ/QR+MM/ML genotypes increased the chance of achieving HDL-C goals (OR=2.81, CI95%=1.35-5.85, P=0.006). CONCLUSIONS: The results of this study show that the Q192R (rs662) and L55M (rs854560) polymorphisms may play a role in interindividual variation in achievement of HDL-C goals in response to statins.

Evaluation of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin therapy in a southern Brazilian cohort.

BACKGROUND: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. OBJECTIVE: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. METHODS: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. RESULTS: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). CONCLUSIONS: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort / Papel do Dimorfismo Sexual na Eficácia e Segurança da Terapia com Sinvastatina ou Atorvastatina em uma Coorte no Sul do Brasil

Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations. .

Fundamento: A dislipidemia é o principal fator de risco para doenças cardiovasculares e as estatinas são efetivas no controle do perfil lipídico. Diferenças sexuais na farmacocinética e farmacodinâmica contribuem para a variação interindividual na eficácia e toxicidade de fármacos. Objetivo: Avaliar a existência de dimorfismo sexual na eficácia e segurança do tratamento com sinvastatina/atorvastatina. Métodos: 495 sujeitos (331 mulheres e 164 homens) tiveram seus níveis lipídicos mensurados antes e após 6±3 meses de tratamento com sinvastatina/atorvastatina para avaliação dos perfis de eficácia e segurança. Resultados: As mulheres apresentaram maiores níveis basais de colesterol total, LDL-C e HDL-C quando comparadas aos homens (p < 0,0001). Após o tratamento, mulheres tiveram uma maior redução dos níveis de colesterol total e de LDL-C que homens. Após ajuste para covariáveis, foi observado que os níveis basais de colesterol total e de LDL-C são responsáveis por cerca de 30% da eficácia (p < 0,001), independentemente do sexo. Mialgia (com ou sem alteração de creatina fosfoquinase - CPK) ocorreu mais frequentemente em mulheres (25,9%) (p = 0,002), enquanto o aumento isolado de CPK e alterações de função hepática foram mais frequentemente observados em homens (17,9%) (p = 0,017). Conclusões: Nossos resultados demonstram que os níveis basais de colesterol total e LDL-C são os maiores preditores da eficácia do tratamento, independente do sexo. Adicionalmente, sugerimos que existe dimorfismo sexual na segurança do tratamento com sinvastatina/atorvastatina. O efeito das diferenças sexuais em receptores, proteínas transportadoras e rotas de expressão gênica devem ser avaliados ...

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy.

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

Influence of PPARA, RXRA, NR1I2 and NR1I3 gene polymorphisms on the lipid-lowering efficacy and safety of statin therapy / Influência de polimorfismos nos genes PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.

OBJETIVO: O objetivo deste estudo foi investigar a associação de seis variantes genéticas nos genes de receptores nucleares PPARA, RXRA, NR1I2 e NR1I3 na eficácia hipolipemiante e na segurança da terapia com estatinas. SUJEITOS E MÉTODOS: O estudo foi realizado com 240 pacientes hipercolesterolêmicos em terapia com sinvastina e atorvastatina. Os polimorfismos foram analisados por meio de métodos baseados em PCR. RESULTADOS: A distribuição da frequência genotípica do polimorfismo NR1I3 rs2307424 foi diferente entre os pacientes com e sem efeito adverso à medicação; entre os sujeitos do grupo com efeitos adversos, nenhum homozigoto T/T foi observado, enquanto no grupo de indivíduos sem efeitos adversos a frequência desse genótipo foi 19,4% (P = 0,007, após correção para múltiplos testes P = 0,042). CONCLUSÃO: Os polimorfismos investigados nos genes PPARA (rs1800206), RXRA (rs11381416) e NR1I2 (rs1523130) não foram associados com eficácia hipolipemiante e segurança da terapia com estatinas. Nossos resultados mostram uma possível influência de variantes do gene NR1I3 (rs2307424) no desenvolvimento de efeitos adversos à terapia com estatinas.